KR19990013983A - Optically Active Alcohols And Methods For Making It - Google Patents

Abstract

R or S-form optically active alcohol of formula (I) and a process for preparing the same, comprising asymmetrically trans-esterifying the corresponding racemic alcohols to effect optical decomposition:

CH ₃ C * H (OH) (CH ₂ ) _m CH (C _n H _{2n + 1} ) ₂

[Wherein, C * is an asymmetric carbon, m is an integer of 0 to 3, n is an integer of 1 to 3].

Description

Optically Active Alcohols And Methods For Making It

The present invention relates to novel secondary optically active alcohols having a methyl group on an asymmetric carbon atom and having side chain alkyl chains having the same number of carbon atoms at the ends, and a process for their preparation.

Optically active compounds have been used in the pharmaceutical and pesticide fields, and have attracted attention as functional materials for ferroelectric liquid crystal and organic nonlinear materials in recent years. For example, in the field of organic nonlinear materials, the molecules of the organic material preferably have asymmetric centers, which can create a second order non-linear optical effect. See, for example, Yamamaguchi, Nakano. ) And Fueno, Kagaku (Chemical) 42 (11), 757 (1987)]. In the field of ferroelectric liquid crystal compounds, it is required that the liquid crystal molecules have an optically active structure so that the liquid crystal compounds can exhibit ferroelectricity [eg, Johno, Fukuda, Journal of Organic Synthesis Chemistry Society, 47 (6). ), 568 (1989).

In addition, in recent years, antiferroelectric liquid crystal compounds have attracted considerable attention, but antiferroelectric liquid crystal compounds are required to have optically active structures like ferroelectric liquid crystal compounds. In the above fields, optically active 2-butanol, 2-octanol, 2-methyl-1-butanol, amino acid derivatives and the like have been used as optically active sources. However, as long as the optically active material is used, the optically active material obtained is limited in its properties.

In the field of ferroelectric liquid crystals, in recent years, attempts have been actively made to synthesize ferroelectric liquid crystal compounds from the following optically active alcohols substituted with perfluoroalkyl groups on asymmetric carbons (C *) [eg JP-A-64-3154, JP-A-1-316339, JP-A-1- 316367, JP-A-1-316372, JP-A-2-225434 and JP-A-2-229128.

(1) CF ₃ C * H (OH) CH ₂ COOC ₂ H ₅

(2) CF ₃ C * H (OH) CH ₂ CH ₂ OC ₂ H ₅

(3) CF ₃ C * H (OH) CH ₂ CH ₂ CH ₂ OC ₂ H ₅

(4) CF ₃ C * H (OH) CH ₂ CH ₂ CH ₂ CH ₂ OC ₂ H ₅

(5) CF ₃ C * H (OH) C ₆ H ₁₃

(6) CF ₃ C * H (OH) C ₈ H ₁₇

(7) C ₂ F ₅ C * H (OH) C ₈ H ₁₇

The ferroelectric liquid crystal compounds derived from the alcohols all have perfluoroalkyl groups with high negative electrons substituted on each asymmetric carbon, providing high spontaneous polarization and also providing relatively fast reaction rates. In addition, since the liquid crystal compound derived from the above (5), (6) or (7) provides a liquid crystal compound having an antiferroelectric phase easily, it can be seen that these alcohols are particularly noticed as characteristic optically active alcohols.

Further, in the method for synthesizing an optically active alcohol of CF ₃ C * H (OH) (CH ₂ ) _m OC _n H _{2n + 1} (wherein m is an integer of 2 to 7 and n is an integer of 1 to 4). On the contrary, the present inventors studied in detail the method of synthesizing a target optically active alcohol having high optical purity, and a liquid crystal compound derived therefrom, without using ethyl trifluoroacetoacetate which is an expensive raw material. It has been found that very useful antiferroelectric liquid crystal compounds or dielectric liquid crystal compounds can be obtained from alcohols (JP-A-5-65486 and JP-A-8-33555).

Even when the antiferroelectric liquid crystal compound or the ferroelectric liquid crystal compound is derived from a selective optically active alcohol having an asymmetric carbon substituted with a fluoroalkyl group, the obtained liquid crystal compound shows very high spontaneous polarization. If the spontaneous polarization is large, the reaction rate is fast, and high spontaneous polarization is advantageous in this respect. However, as the spontaneous polarization increases, the interaction between the array film having the liquid crystal compound in the cell and the heat insulating film increases, and as a result, the deformation of the hysteresis of the electro-optical reaction increases extremely extremely. Therefore, the problem that driving margin is not allowed is likely to be caused.

Therefore, there is a need for a desired liquid crystal compound that exhibits less spontaneous polarization and has no problems with reaction rates and tilt angles.

Optically active secondary alcohols can be prepared in several ways.

However, from an economic performance point of view, using the optically active compound as a raw material is not suitable because the optically active compound is expensive.

On the other hand, optically active alcohols can also be prepared by asymmetric synthesis. For example, one may consider the use of a method of preparing optically active alcohols by preparing the corresponding ketones as precursors and then asymmetrically reducing the ketones in the presence of an asymmetric reduction catalyst. In this case, however, the asymmetric reduction catalyst is very expensive. In addition, it is not always possible to obtain products with high optical purity, only one of the R or S compound is obtained.

For example, there is a known method in which prochiral ketones are asymmetrically reduced in the presence of a catalyst in which (1R, 2R) -1,2-diphenyl-2-aminoethanol is a complex containing a boron atom as a ligand. [J. Yaozhong et al., Tetrahedron: Asymmetry, 5 (7), 1211 (1994)).

The method is very effective for aromatic ketones. However, it cannot be said that it is effective for aliphatic ketones because the enantiomers obtained have very low optical purity.

In another method, it is conceivable to asymmetrically hydrolyze suitable esters which are precursors of optically active compounds such as acetates. Enzymes can be used as effective asymmetric hydrolysing agents. Kitazume et al. Proposed asymmetric hydrolysis of acetate using lipases. T. Kitazume et al., J. Org. 52, 3211 (1987), JP-A-2-282304.

According to Kitazme et al., An acetate of the formula CF ₃ CH (OCOCH ₃ ) C _n H _{2n + 1} is asymmetrically hydrolyzed in the presence of lipase MY in phosphate buffer.

However, the asymmetric recognition ability of lipase MY is highly dependent on the chemical structure of the compound to be hydrolyzed. In addition, the optical purity of the obtained hydrolysis product is very different from 55 to 98 ee% according to the chemical structure shown in Table 1 of Gitazme et al., Supra.

The results show that it is difficult to assess whether the target compound can be effectively asymmetrically hydrolyzed, and it is shown only after the reaction whether the target alcohol having high optical purity can be obtained.

Moreover, there is another significant problem that no asymmetric recognition ability appears at all when some substituents are present on the asymmetric carbon atoms.

For example, lipase MY exhibits very high asymmetric recognition capacity for asymmetric hydrolysis of CF ₃ C * H (OCOCH ₃ ) (CH ₂ ) ₅ OC ₂ H ₅ . However, lipase MY shows no asymmetric recognition of esters of secondary alcohols CH ₃ C * H (OCOCH ₃ ) C ₆ H ₁₃ with a methyl group substituted on an asymmetric carbon atom.

In addition, secondary alcohols are also prepared by optical degradation by asymmetric trans-esterification of the secondary racemic alcohol in the presence of a suitable enzyme.

One example is an asymmetric trans-esterification reaction in the presence of lipase (from pig pancreas) in an organic solvent. See A. M. Klibanov et al., J. Am. Chem. Soc. 1985, 106, 7072.

However, no lipase with any high activity and high enantio-selectivity is known. Optical degradation by asymmetric hydrolysis or asymmetric trans-esterification with enzymes has the advantage of easily obtaining both R- and S-form optically active compounds.

The present invention has been made in view of the above situation, and an object of the present invention is to prepare a novel secondary optically active alcohol having a methyl group on an asymmetric carbon atom and having a branched alkyl chain having the same number of carbon atoms at the terminal and its advantageous preparation To provide a way.

According to the study of the present inventors, it has been found that the above object of the present invention is achieved by a novel R- or S-form optically active alcohol of formula (I):

[Formula 1]

CH ₃ C * H (OH) (CH ₂ ) _m CH (C _n H _{2n + 1} ) ₂

[Wherein, C * is an asymmetric carbon, m is an integer of 0 to 3, n is an integer of 1 to 3].

In the optically active alcohol of Formula 1, the methyl group is substituted on the asymmetric carbon (C *), the side chain alkyl group -CH (C _n H _{2n + 1} ) ₂ is present at the terminal, and two -C _{n2n +} of the side chain alkyl group ₁ has a structural characteristic of being an alkyl group having the same number of carbon atoms. In Formula 1, m is an integer of 0 to 3, n is an integer of 1 to 3, preferably 1 or 2.

According to the study by the inventors, an industrially advantageous method for preparing the optically active alcohol of the formula (1) has been found. That is, according to the present invention, there is provided a method for preparing an optically active alcohol by optical decomposition of racemic alcohol of formula (2), which method performs optical decomposition by asymmetrically trans-esterifying the racemic alcohol. It features.

CH ₃ CH (OH) (CH ₂ ) _m CH (C _n H _{2n + 1} ) ₂

[Wherein m is an integer of 0 to 3, n is an integer of 1 to 3].

In the present invention, vinyl propionate is suitable as the esterifying agent for the asymmetric trans-esterification.

In the present invention, it is preferable to use a lipase derived from Candida antarcia microorganism as a catalyst for asymmetric trans-esterification. As the lipase, an immobilized enzyme produced by immobilizing lipase on porous acrylic resin particles can be suitably used. Immobilized enzyme is commercially available from Novo Nordisk A / S, which can be used as is.

As used herein, lipases derived from Candida antarsia have a very high reactivity per unit, have a high enantio-selectivity, i.e. selectivity for selectively converting the R-body to propionate esters, and porcine pancreas. It has a higher reactivity compared to lipases derived from and Pseudomomas derived lipases which are known to have optical resolution of secondary alcohols. It can show high reactivity even in small amounts.

Since the reaction rate is proportional to the amount of lipase used, the amount is determined by the predetermined reaction time. In general, however, the amount of said lipase per mole of racemic alcohol as precursor is preferably in the range of 0.1 to 10 g.

The reaction temperature of the asymmetric trans-esterification is preferably 20 to 40 ° C. in order to achieve a sufficient reaction rate and sufficient enantioselectivity.

EXAMPLE

The invention is described in detail with reference to the following examples, which are not intended to limit the invention.

Example 1 Preparation of R-(-)-5-methylhexan-2-ol

(Formula 1: m = 2, n = 1 (E1))

(1) Preparation of 5-methylhexan-2-ol (racemic compound)

40 g of 12% NaBH ₄ solution (NaOH aqueous solution) is added dropwise to 40 g of commercial 5-methyl-2-hexanone. The mixture is stirred for 3 hours at room temperature, then water is added and the mixture is extracted with ether. The ether layer is washed with 6 N hydrochloric acid, then washed with water until the ether layer is almost neutral, and the ether layer obtained is further washed with saturated aqueous sodium chloride solution.

The washed ether layer is dried over anhydrous sodium sulfate and the ether is distilled off to yield 35 g of crude product. The crude product is purified by distillation to give the final product (3 Torr, 74 ° C., yield 70%).

(2) Preparation of R-(-)-5-methylhexane-2-propionate

13 g of vinyl propionate and 300 mg of lipase (Novozym 435) immobilized on porous acrylic resin particles are added to 25 g of secondary alcohol obtained in (1), and the mixture is allowed to stand at room temperature for 24 hours. Stir.

After completion of the reaction, the lipase is filtered off and the residue is washed with hexane. Next, hexane, raw alcohol, hexane and the like are distilled off.

The obtained product was purified by silica gel column chromatography to obtain an oily final product (22 Torr, 84 ° C., yield: 65%) and S-(+)-5-methylhexan-2-ol (yield: 80%). To obtain

(3) Preparation of R-(-)-5-methylhexan-2-ol

11 g of R-(-)-5-methylhexane-2-propionate obtained in (2) are added to a solution of 7 g of potassium hydroxide in 20 ml of water / methanol (1/3), and The mixture is stirred at rt for 1 h. After completion of the reaction, the reaction mixture is extracted with ether, the organic layer is washed with water and saturated aqueous sodium chloride solution, and the washed mixture is dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, ether was distilled off to give the final product (20 Torr, 66 ° C., yield: 88%).

Example 2 Preparation of R-(-)-6-methylheptan-2-ol

(Formula 1: m = 3, n = 1 (E2))

The final product is obtained from commercial 6-methylheptan-2-ol by carrying out the same optical decomposition as in Example 1.

Example 3: Preparation of R-(-)-3-methylbutan-2-ol

(Formula 1: m = 0, n = 1 (E3))

R-(-)-3-methylbutan-2-propionate and S-(+)-3-methylbutan-2 from commercial 3-methyl-2-butanol in the same manner as in (2) of Example 1 Obtain a mixture of -ols.

The mixture is dissolved in ether, octanoic acid chloride is added, pyridine is added dropwise and the mixture is stirred at room temperature for 30 hours. 6 N hydrochloric acid is added to the obtained mixture, the mixture is extracted with ether, and the ether layer is washed with water.

The washed ether layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and then R-(-)-3-methylbutane-2-propionate and S-(+)-3-methylbutane by distillation under reduced pressure. 2-octanoate is separated separately.

The above R-(-)-3-methylbutane-2-propionate is treated in the same manner as in (3) of Example 1 to obtain a final product.

Example 4 Preparation of R-(-)-4-methylpentan-2-ol

(Formula 1: m = 1, n = 1 (E4))

By carrying out the same optical decomposition as in Example 3, the final product is obtained from commercial 4-methylpentan-2-ol.

Example 5 Preparation of R-(-)-5-ethylheptan-2-ol

(Formula 1: m = 2, n = 2 (E5))

(1) Preparation of 5-ethylheptan-2-ol (racemic compound)

4.4 g of sodium are dissolved in a solution mixture containing 26 moles of methyl acetate and 60 ml of absolute ethanol and the mixture is cooled to room temperature. 0.17 mol of 3-ethyl-1-butyl bromide is added dropwise to the mixture under stirring, and the obtained mixture is refluxed under heating for 50 hours.

After the obtained reaction mixture is filtered using suction, ethanol is distilled off and the residue is dissolved in 80 ml of 10% aqueous sodium hydroxide solution. The resulting solution is stirred at room temperature for 24 hours and then acidified with concentrated hydrochloric acid. The solution is cooled and then extracted with ether to separate the organic layer.

30 g of 12% NaBH ₄ solution (aqueous NaOH solution) are added to the organic layer over 2 hours. The mixture is stirred at room temperature for 2 hours, water is added and the mixture is extracted with ether. The ether layer is washed with 6 N hydrochloric acid and then with water until the ether layer is almost neutral. In addition, the ether layer is washed with a saturated aqueous sodium chloride solution. The ether layer is dried over anhydrous sodium sulfate and the ether is distilled off under atmospheric pressure to give the crude product. The crude product is purified by distillation under reduced pressure (30 Torr, 103 ° C.) to give racemic alcohol as a final product (0.040 mol, yield: 23%).

The racemic alcohol thus obtained is treated in the same manner as in (2) and (3) of Example 1 to obtain an optically active alcohol as a final product.

Example 6: Preparation of R-(-)-4-ethylhexan-2-ol

(Formula 1: m = 1, n = 2 (E6))

(1) Preparation of 4-ethylhexan-2-ol (racemic compound)

0.270 moles of magnesium metal are placed in a round bottom flask, the atmosphere in the flask is replaced with nitrogen, and then 100 ml of dry tetrahydrofuran are added. 0.110 mol of 1-bromo-2-ethylbutane solution in 100 ml of dry tetrahydrofuran is added to this, and reaction temperature is adjusted to 40 degrees C or less. After the reaction mixture was left for 1 hour, 0.280 mol of acetaldehyde (tetrahydrofuran solution with a concentration of 35%) was added dropwise to adjust the reaction temperature to 50 ° C or lower. The mixture is then reacted at 50 ° C. for 2 hours.

After the reaction was completed, 150 ml of 6N hydrochloric acid was added dropwise, the reaction mixture was stirred at room temperature for 2 hours, and the organic layer was separated. The organic layer is washed with water until it is almost neutral and further washed with saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate, and tetrahydrofuran is distilled off under reduced pressure to give a crude product. The crude product is distilled off under reduced pressure (20 Torr, 75 ° C.) to give racemic alcohol as final product.

The racemic alcohol thus obtained is treated in the same manner as in (2) and (3) of Example 1 to obtain an optically active alcohol as a final product.

Table 1 shows the NMR spectral data of the final products (E1 to E6) obtained in Examples 1-6.

In addition, the final products (E1 to E6) obtained in Examples 1 to 6 were each measured for optical purity by the following method.

The optically active alcohol obtained is converted to acetate by pyridine / acetic anhydride. The obtained acetate is analyzed using an analytical gas chromatograph (CP Cyclodex β236M) of the optically active compound, and the purity of each optically active alcohol is determined based on the peak area ratio of the two enantiomers. In addition, the non-visibility of each optically active alcohol is measured.

Table 2 shows the results.

The present invention can provide a novel secondary optically active alcohol having a methyl group on an asymmetric carbon atom and having a side chain alkyl chain having the same number of carbon atoms at the terminal in high purity, and providing an economical and simple method for its preparation. .

Claims (10)

R- or S-form optically active alcohol of the formula [Formula 1] CH ₃ C * H (OH) (CH ₂ ) _m CH (C _n H _{2n + 1} ) ₂ [Wherein, C * is an asymmetric carbon, m is an integer of 0 to 3, n is an integer of 1 to 3]. The optically active alcohol according to claim 1, wherein n in Formula 1 is 1 or 2. The optically active alcohol according to claim 1, wherein the optically active alcohol is an R-chain. The optically active alcohol according to claim 1, wherein the optically active alcohol is an S-chain. A process for preparing an optically active alcohol by optical decomposition of racemic alcohol of formula (2), wherein the optical decomposition is performed by asymmetrically trans-esterifying the racemic alcohol: [Formula 2] CH ₃ CH (OH) (CH ₂ ) _m CH (C _n H _{2n + 1} ) ₂ [Wherein m is an integer of 0 to 3, n is an integer of 1 to 3]. 6. A process according to claim 5 wherein the asymmetric trans-esterification is carried out in the presence of vinyl propionate as an esterifying agent. A process according to claim 5, wherein asymmetric trans-esterification is carried out in the presence of a lipase from Candida antarcia as a catalyst. 8. The method of claim 7, wherein the lipase is immobilized on the porous acrylic resin particles. 8. The method of claim 7, wherein the lipase is used in an amount of 0.1 to 10 g per mole of racemic alcohol. The process of claim 5 wherein the trans-esterification is carried out at a temperature in the range of 20-40 ° C. 7.